Ruxolitinib improves outcomes in chronic graft-vs-host disease

The oral Janus kinase (JAK) 1/2 inhibitor ruxolitinib may improve outcomes in patients with steroid-refractory or steroid-dependent chronic graft-vs-host disease (GVHD) compared with current best available therapy (BAT), according to results of the phase III REACH3 study presented at ASH 2020.

“This is the first successful randomized phase III trial of ruxolitinib in patients with [steroid-refractory or dependent] chronic GVHD. Ruxolitinib demonstrated superior efficacy vs BAT, measured by a higher overall response rate (ORR), longer failure-free survival (FFS), and greater symptom improvement,” said the authors. In addition, ruxolitinib had a safety profile “consistent with that expected for this drug and this population.”

Participants were 329 patients aged ≥12 years (median age 49 years [12 patients aged <18 years], 61 percent male) with moderate-to-severe steroid-refractory or steroid-dependent chronic GVHD following allogeneic hematopoietic cell transplant. They were randomized 1:1 to receive ruxolitinib (10 mg BID) or a choice from 10 options of investigator-selected BAT for six 28-day cycles, on top of their background corticosteroid therapy with/without calcineurin inhibitors (CNIs).

Patients who did not achieve or maintain complete or partial response to BAT, those who developed toxicity to BAT, and those who experienced a chronic GVHD flare could cross over to receive ruxolitinib from or after day 1 of cycle 7 (C7D1).

Patients who were transitioning from acute to chronic GVHD without tapering of steroids and those who had received ≥2 prior lines of systemic therapy for chronic GVHD plus corticosteroids with/without CNI were excluded.

At data cut-off, 38 percent of patients (n=125) were still on study treatment. Fifty percent of patients on ruxolitinib and 74 percent on BAT discontinued treatment. Thirty-seven percent of those randomized to BAT crossed over to receive ruxolitinib. Reasons for discontinuation in ruxolitinib and BAT recipients included lack of efficacy (15 percent vs 43 percent), adverse events (AEs; 17 percent vs 5 percent), and relapse (5 percent vs 4 percent).

At C7D1, ORR, defined as achievement of complete or partial response, was significantly higher with ruxolitinib compared with BAT (50 percent vs 26 percent; odds ratio [OR], 2.99, 95 percent confidence interval [CI], 1.86–4.80; p<0.0001). [ASH 2020, abstract 77]

Eleven and five patients randomized to ruxolitinib and BAT, respectively, achieved complete response, while 71 and 37, respectively, achieved partial response. 

FFS, ie, time to earliest recurrence, start of new systemic treatment for chronic GVHD, or death, was longer in patients assigned to ruxolitinib vs BAT (median not reached vs 5.7 months; hazard ratio, 0.370, 95 percent CI, 0.268–0.510; p<0.0001).

Modified Lee symptom score (mLSS) responder rate (≥7-point reduction from baseline in total symptom score) was also greater in the ruxolitinib than BAT group (24 percent vs 11 percent; OR, 2.62; p=0.0011).

Mortality rate was comparable between the ruxolitinib and BAT groups (19 percent vs 16 percent), with chronic GVHD the primary cause of death (13 percent vs 8 percent), which included the two deaths that occurred following cross over to ruxolitinib.

At C7D1, AE rates were also similar between the ruxolitinib and BAT arms (98 percent vs 92 percent), with 57 and 58 percent, respectively, grade ≥3 AEs. The most frequently occurring AEs (≥15 percent) in the two groups were anaemia (29 percent vs 13 percent), hypertension (16 percent vs 13 percent), pyrexia (16 percent vs 9 percent), and alanine aminotransferase elevation (15 percent vs 4 percent). Infections occurred in 64 and 56 percent of ruxolitinib and BAT recipients, respectively, 19 and 18 percent, respectively, grade 3 infections. These infections were primarily viral (34 percent vs 29 percent) or bacterial (28 percent vs 26 percent), while 12 and 6 percent, respectively, were fungal infections.

A new hope

Approximately 50 percent of patients are refractory or dependent on systemic corticosteroids, which are among the standard first-line therapies for chronic GVHD. These patients will require additional treatment, though the best second-line therapy has yet to be determined, said the authors.

“The damaging and sometimes deadly effects of chronic GVHD following stem cell transplant present significant treatment challenges, particularly for the nearly half of patients who do not adequately respond to steroid treatment,” said study lead author Professor Robert Zeiser from University Hospital Freiburg, Freiburg, Germany. [https://www.novartis.com/news/media-releases/novartis-announces-first-data-from-reach3-trial-showing-jakavi-ruxolitinib-significantly-improved-outcomes-patients-steroid-resistantdependent-chronic-gvhd]

“Based on the compelling REACH3 results, we now have a potential new standard of care for these patients,” he said.